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Skin Immunity

Arch. Immunol. Ther. Exp. (2018) 66:45–54
Skin Immunity
Agata Matejuk1,2
Received: 14 November 2016 / Accepted: 20 March 2017 / Published online: 16 June 2017
Ó The Author(s) 2017. This article is an open access publication
Abstract Skin is the largest organ of the body with a
complex network of multitude of cell types that perform
plastic and dynamic cellular communication to maintain
several vital processes such as inflammation, immune
response including induction of tolerance and disease
prevention, wound healing, and angiogenesis. Of paramount importance are immunological functions of the skin
that protect from harmful exposure coming from external
and internal environments. Awareness of skin immunity
can provide a better comprehension of inflammation,
autoimmunity, cancer, graft-versus-host disease, vaccination, and immunotherapy approaches. This paper will
update on what we currently know about immune sentinels
contributing to skin immunity.
Keywords Immune response Skin Epidermis Dermis Hypoxia
The skin is not only a physical barrier between external and
internal environments actively protecting from stress caused
by injury, microbial treat, UV irradiation, and environmental
toxins. For a long time, skin was envisioned only as a static
shield separating from external milieu. The concept of skin
immunity and skin-associated lymphoid tissue was
introduced by Streilein (1983) and this concept, although
with caution, has been further extended to nominate skin as a
peripheral lymphoid organ (Egawa and Kabashima 2011;
Ono and Kabashima 2015). Immune system within the skin
is located in both major structural compartments: epidermis
and dermis and consist of several important types of
immunocompetent cells. Main skin-resident immune cells,
Langerhans cells (LCs) together with melanocytes that
produce melanin, occupy epidermis, whereas the other types
of immune specialized cells such as various dendritic cell
(DCs) subpopulations, macrophages, and several T cell types
reside in deeper layer—dermis. The effectiveness of the skin
immune system strongly depends on the close interplay and
communication between immune cells and the skin environment, e.g., neighboring keratinocytes and fibroblasts.
Direct functional success of the skin immunity depends also
on the flexibility of dermal vessels and the lymph nodes that
drain the skin. This complex network ensures the proper
surveillance and communication on which the elimination of
external threat relies on. Homeostasis ends when skin function and integrity are challenged and disease starts when
homeostasis is irreversibly compromised.
During the last years, a new contribution in immune
response for several populations of cells residing different
layers of the skin has emerged. In this paper, the role of
different cellular populations that may change the fate of
skin immunity is discussed.
& Agata Matejuk
[email protected]
Immune Competence in Epidermis
Faculty of Health Science, Wroclaw Medical University,
Wrocław, Poland
Faculty of Science and Technology, Karkonosze College,
Jelenia Góra, Poland
Keratinocytes constitute a major structural element of outer
layer of the skin and depending on the maturation level
create four strata of epidermis. Besides their structural
character, recent studies found unexpected role for keratinocytes in innate and adaptive immunity (Nestle et al.
2009). Modulation of the immune system and the skin
immune status strongly depends on functional keratinocytes. Keratinocytes together with neutrophils and
epithelial cells create a major source of antimicrobial
peptides (AMPs), small cationic and amphipathic molecules, acting as a first line of defense (Harder et al. 1997;
Matejuk et al. 2010). Aberrant AMPs expression leads to
the development of inflammatory skin diseases and susceptibility to microbial infections. Defective function of
some AMPs such as cathelicidin and b-defensins may play
a role in atopic dermatitis lesions (Wollenberg et al. 2011).
Decreased AMP expression leads to increased predisposition to skin infections in atopic dermatitis, whereas high
expression of AMPs is observed in psoriatic lesions (de
Jongh et al. 2005; Ong et al. 2002). It has been found that
cathelicidin coupled with self-DNA activates plasmocytoid
DCs, key players in the pathogenesis of psoriasis (Lande
et al. 2007). Expression of AMPs can be upregulated by
some pro-inflammatory cytokines such as interleukin IL-17
and IL-22 (Liang et al. 2006). Recently, it has been shown
that the cholinergic anti-inflammatory pathway via
acetylcholine downregulates AMPs (Curtis and Radek
2012). One of AMPs, a member of cathelicidin family (LL37), produced by keratinocytes has an essential role in
promoting angiogenesis and wound healing (Zanetti 2004).
Injury increases levels of LL-37 and this process is
dependent on active and functional form of vitamin D3
(Schauber et al. 2007). Keratinocytes express on the surface and within, endosomes Toll-like receptors (TLRs).
Activation of TLRs on keratinocytes promotes Th1
responses and production of interferons (IFNs) (Miller
2008). Keratinocytes are able to generate the production of
classic pro-inflammatory cytokines such as IL-1b and IL18 via inflammasome signalling pathway (Martinon et al.
2009). Inflammasome, a pro-inflammatory machinery, was
found to be activated by UV irradiation (Feldmeyer et al.
2007; Keller et al. 2008). IL-1 produced by keratinocytes
can upregulate expression of intercellular adhesion molecule (ICAM)-1. Upregulation of adhesion molecules on
dermal endothelial cells and MHC class II on keratinocytes
and LCs facilitate leukocyte trafficking into the skin.
Besides IL-1 and IL-18, keratinocytes are able to produce
IL-6, IL-10, and tumor necrosis factors (TNFs). Moreover,
plasticity of keratinocytes in production of chemokines and
chemokine receptors empowers them to communicate and
cooperate with other cell types during immune response. In
disease conditions with abundant infiltration of T cells such
as psoriasis, keratinocytes express several chemokine
ligands such as CXCL9, CXCL10, CXCL11, and CCL20
(Albanesi et al. 2005). The latter selectively attracts
Arch. Immunol. Ther. Exp. (2018) 66:45–54
precursors of LCs into epidermis (Dieu-Nosjean et al.
2000). Upregulated levels of CXCL1 and CXCL8 by keratinocytes signal neutrophils for epidermis infiltration
(Albanesi et al. 2005). Studies on graft-versus-host disease
revealed that keratinocytes upon stimulation with IFN-c
can express MHC class II, thus may play a role as antigenpresenting cells (APCs) for T cell infiltrates (Nickoloff and
Turka 1994). Keratinocyte involvement in crosstalk with T
cells is evident. Studies show that depending on the stimuli
and cellular environment, keratinocytes possess ability to
induce T cells activation or antigen-specific tolerization.
Keratinocytes are not able to prime naı̈ve T cells; however,
they can stimulate antigen experienced CD4 and CD8 cells
(Black et al. 2007). Malfunction of keratinocytes leads to
pathological conditions such as autoimmunity and cancer.
With upregulation of CD40 ligand on keratinocytes, the
number of LCs drastically decreases and the number of
dermal DC (dDC) increases with a strong effect on tolerance disruption to skin antigens (Mehling et al. 2001).
Redistribution of LCs and cd cells in skin caused by acute
as well as constitutive expression of retinoic acid early
transcript 1 on keratinocytes can directly lead to cancer
(Jones et al. 2008; Oppenheim et al. 2005). Interestingly,
Notch1 a proto-oncogene expressed by most cancers has
adverse consequences in epidermis (Koch and Radtke
2007). Reduction in Notch signalling within keratinocytes
leads to defective skin barrier and development of skin
tumors upon exposure to UV radiation (Demehri et al.
Langerhans’ Cells
Considering the localization of LCs which is the outer part
of the skin in comparison with other types of DCs suggests
their role as first line fighters. Recent studies, however,
confirm the involvement of LCs in tolerogenic responses
rather than those promoting inflammation (Kaplan et al.
2008; Shklovskaya et al. 2011). Suppressive effects of LCs
on contact hypersensitivity depend on their IL-10 production and induction of CD4? regulatory T cells (Yoshiki
et al. 2009) and tolerizing CD8? T cells (Gomez de Aguero
et al. 2012). Nevertheless, the role of LCs in skin immune
responses stays somewhat enigmatic. For a long time,
lectin Langerin (CD207) that induces the formation of
Birbeck granules, characteristic structures for LCs, served
as a marker for human and murine LCs (Valladeau et al.
2000). Recently, Langerin has also been shown to be
expressed by dDC which constitutes distinct population of
cells (Ginhoux et al. 2007; Nagao et al. 2009; Poulin et al.
2007) and is characteristic for most connective and
mucosal tissues and co-exists with classic DCs Langerin
negative. Besides Langerin, Langerhans cells can be recognized by other markers such as CD45, MHC class II
Arch. Immunol. Ther. Exp. (2018) 66:45–54
molecules, E-cadherin, and epithelial-cell adhesion molecule (Borkowski et al. 1996; Stingl et al. 1980; Tang et al.
1993). CD1a molecule is exclusively expressed on human,
but not murine LCs (Romani et al. 2006) and is able to
present microbial nonpeptide antigens to T cells (Hunger
et al. 2004). Mannose receptor CD206 distinguishes a
subset of inflammatory dendritic epidermal cells from LCs
(Guttman-Yassky et al. 2007). Interesting feature of LCs in
the steady state is their ability to repopulate locally independently on the circulating precursors (Stoitzner et al.
2005). Their migratory rate through the dermal lymphatic
vessels to the skin-draining lymph nodes increases during
inflammation (Nishibu et al. 2006). Upon stimulation, LCs
elongate their dendrites that enter epidermal tight junctions
to capture antigens (Kubo et al. 2009). They maturate and
finally localize in the T cell area by upregulating MHC
class II molecules, co-stimulatory molecules (CD40), and
essential for migration CCR7 chemokine receptor (Larsen
et al. 1990; Ohl et al. 2004; Pierre et al. 1997). LCs are
crucial for capturing protein antigens and mediation of Th2
local environment. Permanent LCs depletion results in
decreased IgE serum levels (Nakajima et al. 2012). LCs
have been found to be superior to dDCs in effective CD70mediated CD8? T cells responses to virus, with little or no
effect on bacteria (van der Aar et al. 2011). However, it
seems that both LCs and dDCs can resemble each other
upon inflammatory reactions (Noordegraaf et al. 2010;
Zahner et al. 2011) and the outcome of immune response
most likely depends on the number and not the type of DCs
(Romani et al. 2010). Except for hypersensitivity skin
inflammation models such as cutaneous leishmaniasis, LCs
are negative immune regulators (Kautz-Neu et al. 2011).
The most recent studies show that in case of Candida
albicans infection, the morphology of the pathogen dictates
the proper responses by LCs or dDC subsets (Igyarto et al.
2011; Kashem et al. 2015).
Immune Competence in Dermis
Dermal DCs
In contrast to LCs that occupy epidermis, dDCs reside in
dermis below the epidermal–dermal junction, and are distinguished by the expression of epithelial-cell adhesion
molecule, IL-10, and ability to stimulate B cells into
plasma cells secreting IgM (Dubois et al. 1999). Expression
of low-density lipoprotein-related protein 1 (or CD91) is
also characteristic for dDCs (Boyman et al. 2005). The
plasticity of dDCs is remarkable and depending on the
function, sublocalization, and environment, they create
phenotypically diverse group of cells (Henri et al. 2010;
Malissen et al. 2014; Tamoutounour et al. 2013). The main
two types of dDCs are: Langerin?CD103? DCs, which are
similar to mouse CD8? cross-presenting DCs in lymphoid
organs (Bedoui et al. 2009) and Langerin negative dDCs.
Within the latter, at least three DCs populations were
identified in the murine dermis: monocytes-derived DCs
with CCR2?CD64low/? phenotype and two populations of
dermal conventional DCs that originate from blood-borne
precursors: a subpopulation with CD11b expression and the
double negative XCR1-CD11b- subpopulation (Auffray
et al. 2009; Lopez-Bravo and Ardavin 2008). Dermal DCs
can persist in immature state with expression of TLR2,
TLR4, CD206, and CD209 (Angel et al. 2007) or mature
state with expression of CD83 co-stimulatory molecule and
low levels of TLRs. Main role for dDCs is to provide
immunosurveillance against pathogens by participation in
inflammatory responses via arranging efficient cytokine
and chemokine network (Guttman-Yassky et al. 2007).
DCs that produce both TNF-a and iNOS might play a
major role in psoriasis induction (Lowes et al. 2005; Serbina et al. 2003). In addition, the positive correlation
between IL-23/IL-17/IL-22 axis and psoriasis development
has been demonstrated (Krueger et al. 2007; Leonardi et al.
2008; Zaba et al. 2007a). However, there is a controversy
which subset of DCs is a key player in psoriasis (Glitzner
et al. 2014; Wohn et al. 2013; Yoshiki et al. 2014). Tortola
et al. (2012) identified IL-36, a novel member of IL-1
family that allows DCs-keratinocytes crosstalk during IL23/IL-17/IL-22-dependent immune responses. It has also
been found that in psoriasis, an important role plays LL37,
an AMP that breaks tolerance to self-DNA (Lande et al.
2007). This triggers (infrequent in healthy skin) plasmocytoid DCs, strong producers of type I IFNs (Nestle et al.
2005). In consequence, myeloid DCs are activated and
adaptive immune responses are induced (Boyman et al.
2007). It has been found that DCs and tissue-resident
macrophages have common precursors. Inflammatory
monocytes with CD115?LY6C?LY6G?CCR2? phenotype
differentiate into inflammatory DCs and monocytes with
LY6C-LY6G-CX3CR1? phenotype transform into activated macrophages in mice; in humans, inflammatory
monocytes belong to CD14?CD16- circulating monocytes
(Auffray et al. 2009). A subpopulation of dDCs, macrophage-like cells expressing factor XIIIa and CD163 typical
for macrophages, might play a key role in wound healing
(Zaba et al. 2007b). The complexity of the network created
by dendritic cells, monocytes, and macrophages in the skin
assures effective immunosurveillance and highly diverse
immune response.
Mast Cells
Mast cells are mainly located in the upper dermal part of
the skin, where they can easily encounter, respond, and
protect from infections, venoms, and stress caused by
wound healing. Mast cells contain histamine and traditionally are known as typical allergy cells. Nevertheless,
recent studies prove their remarkable internal and external
plasticity and critical role in vital processes such as wound
healing, skin inflammation, angiogenesis, immune tolerance, and cancer (Galli and Tsai 2010; Moon et al. 2010;
Tsai et al. 2011). In the human skin, there is a prevalence of
mast cells TC type (tryptase positive, chymase positive)
which is the richest in proteinase content. Besides tryptase,
they contain chymase, carboxypeptidase, and a cathepsin
G-like proteinase (Douaiher et al. 2014; Weidner and
Austen 1993). Tryptase works on fibronectin and by
degrading extracellular matrix proteins (Kaminska et al.
1999) allows immune cells such as neutrophils, mononuclear cells, and lymphocytes to invade epidermis. Its
function in the activation and recruitment of the immunecompetent cells (Li and He 2006; Malamud et al. 2003;
Wang and He 2006) is further confirmed by its activatory
effects on keratinocytes and metalloproteinases (Buddenkotte et al. 2005; Iddamalgoda et al. 2008; Sharlow
et al. 2000). The enzyme has also strong proangiogenic
activity (Blair et al. 1997). Similar pro-inflammatory action
is characteristic for another potent mast cell enzyme,
chymase. Chymase has been shown to attract and activate
several immune cells (He and Walls 1998; Terakawa et al.
2006) and increase inflammation by its effect on IL-1b and
IL-18 (Mizutani et al. 1991; Omoto et al. 2006). In addition
to mast cells plasticity, both enzymes were found to downregulate immune response by ability to disintegrate several
pro-inflammatory factors such as cytokines and chemokines (Pang et al. 2006; Zhao et al. 2005). Besides indirect
modulation of immune response by mast cells via secreted
enzymes, they also affect immune-competent cells by
direct cell–cell contact or cytokines. Their strong influence
on different subpopulations of T cells including regulatory
T cells (Treg) was observed via mast cells expression of
OX-40L and TNF-a production (Nakae et al. 2005; Piconese et al. 2009). OX-40L positive mast cells and their
production of TNF-a in combination with T cells derived
IL-6 create classic milieu for tissue inflammation. In
chronic skin inflammation such as psoriatic lesion and
atopic dermatitis, mast cells secrete other cytokines such as
IL-4 and/or IFN-c that shape the immune response (Ackermann et al. 1999; Horsmanheimo et al. 1994). In cancer,
mast cells can express CD30L (Molin et al. 2001) leading
to uncontrolled immune response. Besides known FceRI
receptor involved in allergic response, skin mast cells also
express FccRI and FccRIIa receptors involved in IgG
responses (Malbec and Daeron 2007; Zhao et al. 2006).
Biological responses of mast cells depend on the balance
between positive and negative signals that are generated in
FcR complexes (Malbec and Daeron 2007). Another level
Arch. Immunol. Ther. Exp. (2018) 66:45–54
of communication with other cells and pathogen antigens
can be achieved by mast cells via expression of TLRs
(Dawicki and Marshall 2007). Additional level of complexity and further involvement of mast cells in immune
system are demonstrated by fact that they can behave and
function like professional APCs. First, they can express
MHC class I and class II; second, they facilitate antigen
presentation by expression of co-stimulatory molecules
such as CD80 and CD86; and third, they can migrate to
lymph nodes, where they further affect T cells gathering
(Frandji et al. 1996; Hershko and Rivera 2010; Wang et al.
1998). Moreover, close interaction between mast cells and
professional APCs such as DCs and LCs is essential for
APCs to migrate, maturate, and present the antigen. This
effect is linked to TNF-a and histamine produced by mast
cell as well as their ability to accumulate exogenous antigens within endosomes (Kitawaki et al. 2006; Skokos et al.
2003; Suto et al. 2006). Recently, it has been shown that
mast cells can shape and regulate immune response by
ability to induce immune tolerance. A key player in this
tolerance induction is anti-inflammatory cytokine IL-10
and to the laser extent transforming growth factor (TGF)-b
released by mast cells. IL-10 has been shown to inhibit
inflammatory skin reaction in contact hypersensitivity and
UV-induced immunosuppression (Biggs et al. 2010; Byrne
et al. 2008). The latter can be explained by UV effect on
inhibition of germinal center formation and T helper (Th)
function which in combination with IL-10 derived from
mast cells creates immunosuppressive environment (Chacon-Salinas et al. 2011). Mast cells were shown to increase
number of regulatory T cells (CD4?CD25?Foxp3?) via
TGF-b-dependent mechanism (Zhang et al. 2010). The
ability of mast cells to induce immunosuppression and
angiogenesis as well as rearrangement of extracellular
matrix is pivotal for their role in cancer. In skin cancer
caused by UV irradiation, mast cells can be effectively
attracted by upregulation of Kit receptor and tumor derived
stem-cell factor (SCF) (Huttunen et al. 2002). The importance of Kit–SCF interaction for carcinoma perseverance
was further documented in hepatocarcinoma, where
increase in number of CD11b positive myeloid-derived
suppressor cells and regulatory T cells as well as their IL-9
production was observed (Huang et al. 2008; Yang et al.
T Cell Subsets
It is not a common knowledge that the skin is a reservoir of
approximately 20 billion T cells, nearly twice the number
present in the entire blood volume (Clark et al. 2006).
Initially, the perception of skin immunosurveillance was
based on T cells that migrate between skin-draining lymph
nodes and peripheral tissues. Local defective migration of
Arch. Immunol. Ther. Exp. (2018) 66:45–54
specific T cells rather than systemic decline in T-cell-mediated immunity is responsible for weaker DTH responses
to bacterial, fungal, and viral antigens (Agius et al. 2009).
Studies show that decrease in TNF-a secretion by macrophages inhibits activation of endothelial cells by
suppression of E-selectin, vascular cell adhesion molecule,
and ICAM expression, thus transmigration of T cells into
the skin (Agius et al. 2009). However, the resident rather
than recruited T cells creates skin immune homeostasis. T
cell skin homing properties are obtained after imprinting
process based on contact with skin DCs and mesenchymal
cells (Edele et al. 2008; Mora et al. 2005). Some significant
role in this process is attributed to vitamin D (Sigmundsdottir and Butcher 2008). Vitamin D has been found to
inhibit effector T cell reactivity and induce regulatory T
cells and their homing to sites of inflammation based on its
critical role in AMPs production (Baeke et al. 2011).
Epidermal CD8? ab T cells are of memory phenotype (Bos
et al. 1987) and live among keratinocytes with preferential
localization near LCs (Foster et al. 1990). Equal numbers
of CD4? and CD8? T cells restricted to capillaries and the
epidermal–dermal junction are characteristic for dermis
(Mueller et al. 2013; Nomura et al. 2014). Most of them are
memory cells expressing cutaneous lymphocyte-associated
antigen. Skin memory T cells hold strategic position and
create the first line of defense against pathogen challenge
(Schenkel and Masopust 2014). They express CD103 and
very late antigen 1 and after infectious recall undergo
homeostatic proliferation (Gebhardt et al. 2009). Th17
together with Th1 and Th2 cells are important effector cells
in inflammatory skin pathology such as allergic inflammation (Boyman et al. 2004; Conrad et al. 2007; Honda
et al. 2013; Kim et al. 2013) or psoriasis (Conrad et al.
2007). IL-17 together with IL-22 produced by Th17 cells
have well-documented role in psoriasis by inducing
abnormal differentiation of keratinocytes. Nevertheless,
Th17 cells protect skin from bacteria and fungi such as
Candida albinos, Klebsiella pneumonia, and Staphylococcus aureus (Kashem et al. 2015; Kurebayashi et al. 2013).
The magnitude of immune responses in skin is efficiently
controlled by regulatory T cell (Tregs). They comprise of
5–10% of all resident skin T cells (Clark et al. 2006;
Vukmanovic-Stejic et al. 2008). Together with other resident T cells, Tregs actively circulate between the skin and
lymph nodes not only during immune response but also in
the steady state (Clark 2010; Tomura et al. 2010). They can
regulate T cell responses, function of APCs such as DCs
and macrophages as well as neutrophil accumulation during early stages of inflammation (Richards et al. 2010;
Schwarz and Schwarz 2010; Tiemessen et al. 2007). Tregs
have been shown to induce anti-inflammatory functional
profile in macrophages and inhibit macrophage TNF-a
production (Tiemessen et al. 2007). It has been well
documented that immunosuppression by Tregs is directly
related to cancer. Primary and metastatic melanoma contain significant numbers of suppressor T cells, and in
human squamous cell carcinoma of the skin, 50% of T cells
are Foxp3 positive (Ahmadzadeh et al. 2008; Clark et al.
2008; Kaporis et al. 2007). Topical treatment with the
TLR7 agonist increased E-selectin expression and reduced
function and abundance of Tregs (Clark et al. 2008).
Foxp3? Treg depletion induced partial regression of
established B16 melanoma in mice and accumulation of
cytotoxic CD8? T cells (Klages et al. 2010). Tregs were
shown to inhibit Fas ligand-induced innate and adaptive
tumor immunity in similar model and their removal
improved tumor rejection (Simon et al. 2007).
Unconventional or innate resident T cells belong to cd T
cells and NKT cells (Hayday and Tigelaar 2003; Kronenberg 2005). Unlike naı̈ve ab T lymphocytes, skin cd T cells
reside in the epidermis in a pre-activated state. In mice,
90% of all T cells in epidermis are Vc5? dendritic epidermal T cells (Bergstresser et al. 1985). They provide
immunoregulation and control over ab T-cell-mediated
inflammation (Boyden et al. 2008; Girardi 2006). In contrast to ab T cells, cd T cells inhibit skin tumor responses
(Girardi et al. 2001, 2002; Roberts et al. 2007). Human cd
T cells are attributed to the regulation of epithelial homeostasis, cutaneous malignancy, and contact hypersensitivity
(Holtmeier and Kabelitz 2005). Recent finding shows that
IL-23 responsive dermal cd T cells are the major IL-17
producers and may represent a novel target for the treatment of psoriasis (Cai et al. 2011). Moreover, skin cd T
cells act as primary responders to damage and wound
repair due to their ability to produce growth factors participating in wound repairing (Toulon et al. 2009). Skin cd
T cells are able to produce certain AMPs such as cathelicidins allowing antimicrobial defense (Agerberth et al.
2000). The role in antimicrobial immune responses is also
attributed to skin invariant NKT cells which can recognize
bacterial glycolipids (Kronenberg 2005). Self-derived
glycolipids recognized by CD1d-restricted NKT cells
might activate keratinocytes and induce tissue pathology
such as psoriatic plaques and allergic contact dermatitis
(Bonish et al. 2000; Gober et al. 2008; Nickoloff et al.
2000). Activated NKT cells can maintain high levels of
TNF-a and increase DCs migration from the skin to
draining lymph nodes in a mouse model of hypersensitivity
(Gorbachev and Fairchild 2006).
Conclusion and Future Remarks
Current knowledge on immune-competent cells in the skin
highlights the importance of the skin as a part of lymphatic
system. The immune reactions that take place in periphery
organ such as skin are equally important then those
occurring within classical lymphoid organs in protection
from the treath. In the era of vaccination and growing
awareness of cancer, autoimmunity, and aging processes,
the knowledge of skin immunity is of principal significance. Of high importance to our understanding of the skin
immune response is the realization that this organ is
characterized by diverse and low oxygen pressure (Grillon
et al. 2012). Thus, more attention should be paid to environmental factors such as hypoxia, the low oxygen pressure
that is divergent in different layers of the skin and governs
immune reactions in this organ. Immune cells respond to
low oxygen pressure in a different ways depending on the
cell type. Skin hypoxia promotes the survival, recruitment,
and activation of innate immune cells, whereas inhibits
effector lymphocyte functions. Transcription factor
hypoxia-inducible factor (HIF)-1a is the key regulator of
cellular adaptation to hypoxia. HIF-1a plays a role in
bactericidal capacity of macrophages and neutrophils. It
has been shown that HIF-1a regulates the production of
cathelicidin by keratinocytes, thus is crucial for their
antibacterial function (Peyssonnaux et al. 2008). In case of
DCs, hypoxic microenvironment exerts a sharp pressure to
allow pro-inflammatory and antimicrobial functions.
Hypoxia has also a strong influence on sugar-binding
properties by lectins which are imperious in immune
recognition mechanisms, and in case of galectin-1 enhances carbohydrate binding. Expression of Langerin, a C-type
lectin, creates a main characteristic for different subpopulation of skin DCs including LCs and a common
antigen/pathogen recognition receptor (Stoitzner and
Romani 2011). Another imperious factor that should be
considered in our understanding of skin immunity is aging.
Skin aging is a multifactorial process that involves defect
in the function of skin immune cells. Increase in cutaneous
infections and cancer becomes prominent in older humans.
It has been suggested that both acquired and innate
immunity are compromised with age. A substantial role in
suppression of innate and acquired immune responses is
attributed to Tregs. Older individuals have increased
number of Tregs in normal skin. In general, older subjects
are characterized by reduced cutaneous DTH responses and
decreased infiltration of T cells (Castle et al. 1990; Toichi
et al. 1997; Vissinga et al. 1990).
Understanding the mechanisms of skin immunity in
different environmental settings will allow better therapeutic approaches both in dermatology and cosmetical
industry. Recently, there is a growing interest in new and
especially natural compounds with antioxidant and
immunity boosting or diminishing properties that are
promising in prevention from skin disease and premature
Arch. Immunol. Ther. Exp. (2018) 66:45–54
Compliance with ethical standards
Conflict of interest The author declare that she has no conflict of
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